Abstract
BackgroundTransforming growth factor beta1 (TGFB1) is a multi-functional cytokine that regulates mammary gland development and cancer progression through endocrine, paracrine and autocrine mechanisms. TGFB1 also plays roles in tumour development and progression, and its increased expression is associated with an increased breast cancer risk. Macrophages are key target cells for TGFB1 action, also playing crucial roles in tumourigenesis. However, the precise role of TGFB-regulated macrophages in the mammary gland is unclear. This study investigated the effect of attenuated TGFB signalling in macrophages on mammary gland development and mammary cancer susceptibility in mice.MethodsA transgenic mouse model was generated, wherein a dominant negative TGFB receptor is activated in macrophages, in turn attenuating the TGFB signalling pathway specifically in the macrophage population. The mammary glands were assessed for morphological changes through wholemount and H&E analysis, and the abundance and phenotype of macrophages were analysed through immunohistochemistry. Another cohort of mice received carcinogen 7,12-dimethylbenz(a)anthracene (DMBA), and tumour development was monitored weekly. Human non-neoplastic breast tissue was also immunohistochemically assessed for latent TGFB1 and macrophage marker CD68.ResultsAttenuation of TGFB signalling resulted in an increase in the percentage of alveolar epithelium in the mammary gland at dioestrus and an increase in macrophage abundance. The phenotype of macrophages was also altered, with inflammatory macrophage markers iNOS and CCR7 increased by 110% and 40%, respectively. A significant decrease in DMBA-induced mammary tumour incidence and prolonged tumour-free survival in mice with attenuated TGFB signalling were observed. In human non-neoplastic breast tissue, there was a significant inverse relationship between latent TGFB1 protein and CD68-positive macrophages.ConclusionsTGFB acts on macrophage populations in the mammary gland to reduce their abundance and dampen the inflammatory phenotype. TGFB signalling in macrophages increases mammary cancer susceptibility potentially through suppression of immune surveillance activities of macrophages.
Highlights
Transforming growth factor beta1 (TGFB1) is a multifunctional cytokine with diverse roles in the regulation of cellular function, including proliferation, differentiation, migration, apoptosis and the immune response[1,2,3]
Macrophages detected in single transgenic control doxycycline-treated Cfms-responsive transactivator (rtTA) and TetO-TbrII mice exhibited co-localisation with pSMAD2 (1a-c and 1d-f, respectively) whilst there was little co-localisation detected in Cfms-TbrII mice (Fig. 1g–i)
Single-stained controls exhibited little to no staining in the green channel (F4/80 only) or red channel (Supplementary Figure S1) There were significantly less pSMAD-positive macrophages in Cfms-TbrII mice compared to Cfms-rtTA and TetO-TbrII controls (Fig. 1j)
Summary
Transforming growth factor beta (TGFB1) is a multifunctional cytokine with diverse roles in the regulation of cellular function, including proliferation, differentiation, migration, apoptosis and the immune response[1,2,3]. In the early stages of tumourigenesis, TGFB1 acts as a tumour suppressor, through inhibition of cell proliferation, induction of apoptosis and suppression of growth factor, cytokine and chemokine production. Tumour cells can express abundant TGFB1 which appears to have largely pro-tumorigenic effects. This overexpression of TGFB1 by tumour cells modulates epithelial-mesenchymal transition, impairs immune surveillance and promotes angiogenesis, promoting tumour invasion and metastasis. Transforming growth factor beta (TGFB1) is a multi-functional cytokine that regulates mammary gland development and cancer progression through endocrine, paracrine and autocrine mechanisms. This study investigated the effect of attenuated TGFB signalling in macrophages on mammary gland development and mammary cancer susceptibility in mice
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